Evidence for the in Vitro Bioactivation of Aminopyrazole Derivatives: Trapping Reactive Aminopyrazole Intermediates Using Glutathione Ethyl Ester in Human Liver Microsomes was written by Ryan, Eileen;Morrow, Benjamin J.;Hemley, Catherine F.;Pinson, Jo-Anne;Charman, Susan A.;Chiu, Francis C. K.;Foitzik, Richard C.. And the article was included in Chemical Research in Toxicology in 2015.Category: pyrazoles-derivatives This article mentions the following:
Drug-induced toxicity is a leading cause of drug withdrawal from clin. development and clin. use and represents a major impediment to the development of new drugs. The mechanisms underlying drug-induced toxicities are varied; however, metabolic bioactivation to form reactive metabolites has been identified as a major contributor. These electrophilic species can covalently modify important biol. macromols. and thereby increase the risk of adverse drug reactions or idiosyncratic toxicity. Consequently, screening compounds for their propensity to form reactive metabolites has become an integral part of drug discovery programs. This screening process typically involves identification of structural alerts as well as the generation of reactive metabolites in vitro in subcellular hepatic fractions, followed by trapping the reactive species with nucleophiles and characterization via LC-MS. This article presents evidence for the bioactivation of a series of aminopyrazole derivatives via LC-MS detection of glutathione Et ester-trapped reactive intermediates formed in human liver microsomal incubations. These results indicate that the aminopyrazole motif, within specific contexts, may be considered a new structural alert for the potential formation of reactive metabolites. In the experiment, the researchers used many compounds, for example, 3-Methyl-4-nitro-1H-pyrazole (cas: 5334-39-4Category: pyrazoles-derivatives).
3-Methyl-4-nitro-1H-pyrazole (cas: 5334-39-4) belongs to pyrazole derivatives. The strategies for the synthesis of pyrazoles generally can be applied for the construction of indazoles. The presence of both electronegative nitrogen atoms in the pyrazole ring reduces the electron density of the C3- and C5-positions leaving electron density of C4-position unaltered. Thus the C4-position is vulnerable to electrophilic attack. The C3 electrophilic-position may undergo deprotonation in the presence of a strong base leading to ring opening.Category: pyrazoles-derivatives
Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics